16 May 2012. In one of the last sessions of the 2012 Schizophrenia International Research Society meeting in Florence, Italy, a group of diehards heard a series of talks on Wednesday afternoon exploring the potential of oxytocin as a treatment for schizophrenia. Popularly known as the “trust hormone,” oxytocin is a neuropeptide that elicits social behaviors in a wide range of species, including humans. Spritzing oxytocin intranasally appears safe in humans, and it can enhance feelings of trust—a feature that has spurred numerous studies to investigate oxytocin as a remedy for social deficits in a variety of disorders, including schizophrenia. One of the speakers, Cort Pedersen of the University of North Carolina at Chapel Hill argued that social dysfunction is one of the most debilitating features of schizophrenia, yet one that antipsychotic medications don’t touch.

The speakers presented work in progress on oxytocin’s effects on a veritable alphabet soup of assessments of social cognition, but also on core clinical symptoms like psychosis, and behavioral functioning in the real world. This gave a checkered pattern of results suggesting that the context in which oxytocin is delivered may prove important. Several speakers noted that a “therapeutic alliance” between oxytocin and targeted social skill training may make maximal use of oxytocin’s effects. “This is where it’s got to go,” Pedersen said.

Emotion recognition
The diverse lot of social difficulties faced by a person with schizophrenia might stem in part from deficits in emotion recognition. Bruno Averbeck of the National Institutes of Mental Health, Bethesda, Maryland, presented his results finding that subjects with schizophrenia perform worse than controls when trying to correctly identify the emotion on a person’s face in a photograph from six choices: happiness, surprise, fear, sadness, disgust, and anger (Averbeck et al., 2011).

In a new error analysis, Averbeck's group finds that control subjects frequently mistake anger for disgust, or fear for sadness, though they are more accurate with other emotions. People with schizophrenia do not make such specific mistakes, as they make errors on a wider range of emotional expressions, and give a wider range of erroneous responses to anger and fear expressions. Averbeck reported that intranasal oxytocin slightly improved emotion recognition compared to placebo in subjects with schizophrenia, and also induced a consistent pattern of errors similar to that seen in untreated controls.

Noting that people with schizophrenia tend to avoid the signal-rich eyes when looking at faces, Averbeck hypothesized that the neural circuitry that drives attention to social stimuli is not working properly in the disorder. To test this idea, he has begun studies in macaque monkeys, and finds that intranasal oxytocin increases their fixation on eyes in images of faces.

Oxytocin takes on PANSS
Looking beyond emotion recognition, Cort Pedersen addressed whether oxytocin might touch other core features of the disorder, including positive and negative symptoms. For example, if oxytocin increases feelings of intrapersonal trust, could it temper the classic paranoia symptoms? Pedersen gave a talk on behalf of David Feifel of the University of California, San Diego, who had become stranded en route to Florence. Feifel’s study found that three weeks of intranasal oxytocin could improve Positive and Negative Syndrome Scale (PANSS) scores compared to placebo in 15 patients with schizophrenia who continued taking their usual antipsychotic medication (Feifel et al., 2010). This revealed a 7 percent decrease in total PANSS scores when taking oxytocin, with improvements in both positive and negative symptom subscales. The study had a crossover design in which each person took oxytocin and placebo at different points in time, and those taking oxytocin first had a larger effect than those receiving placebo first, which suggests some delayed onset of oxytocin’s actions; similarly, no significant differences emerged before three weeks. Cognitive effects were also found with oxytocin, with improvements in verbal memory measured with the California Verbal Learning Test (CVLT).

In the next talk, Pedersen presented his own findings from a trial consisting of placebo (n = 11) and oxytocin (n = 14) groups of patients with schizophrenia who continued taking their antipsychotic medication. Pedersen measured PANSS scores, but also focused heavily on aspects of social cognition, testing for Theory of Mind (a person’s ability to infer the mental states of others), recognizing trustworthiness, and tracking a PANSS-derived social score that combines scores on the suspiciousness, hostility, social withdrawal, and uncooperativity items. After two weeks, the oxytocin group exhibited significant improvements on this PANSS social score, in addition to the PANSS total, positive, and negative scores, and general paranoia.

Qualifying these results as “tentative,” given the small sample size and short treatment duration, Pedersen then presented results from six weeks of treatment with oxytocin (n = 16) or placebo (n = 13) in participants with schizophrenia. This confirmed the PANSS-based improvements with oxytocin, but over this longer time period, the placebo group made some gains, too. In this light, oxytocin-specific improvements were made in the PANSS negative symptom score, social score, and suspiciousness score. In terms of social cognition, Pedersen reported some improvements in the Theory of Mind tests, and deception recognition with oxytocin, but no consistent effects in tests of empathy (Interpersonal Reactivity Index) or emotion recognition. Effects could be subtle, however, with consistent differences between six-week time points and baseline not always translating into significant differences between placebo and oxytocin groups. Looking to real-life social function, Pedersen found that subjects taking oxytocin rated themselves higher than those taking placebo in the Specific Levels of Functioning (SLOF) measures that pick up on behavioral function and daily living skills. However, informants who knew the patients well did not score them as improved.

Pedersen later noted that the two-week trial was conducted in the hospital, providing a potentially more controlled setting (with respect to timing of oxytocin treatment, or a smaller social milieu, with consistent feedback from staff) than the longer trial, which is conducted in an outpatient setting, and that this may contribute to the complicated pattern of results.

Curiouser and curiouser
Contributing to this more complicated picture of oxytocin’s actions, Heidi Wehring of the University of Maryland in Baltimore described results from a just-completed study of a three-week course of oxytocin in schizophrenia conducted with her advisor, session co-chair Deanna Kelly. Compared to the placebo group (n = 15), those taking oxytocin (n = 13) (in addition to their usual antipsychotic medication) did not exhibit any improvements in social cognition or function, as measured by a battery of assessments different from Pedersen’s (Mayer-Salovay Caruso Emotional Intelligence Test and the Maryland Assessment of Social Competence). Interestingly, negative symptoms (measured with the Scale for Assessment of Negative Symptoms) were improved under oxytocin when delivered to participants in the hospital, suggesting again that the context in which it is delivered may matter. Wehring also reported a curious effect on odor discrimination, with the oxytocin treatment group correctly identifying odors as pleasant, unpleasant, or neutral more accurately than the placebo group.

Leah Rubin of the University of Illinois at Chicago reported a more naturalistic study in which she tracked oxytocin levels in 50 people with schizophrenia. Oxytocin levels did not fluctuate over a woman’s menstrual cycle, but they did correlate with symptoms scores: women with high oxytocin levels had less severe positive and general PANSS scores, and both women and men with high oxytocin levels had higher pro-social scores. Oxytocin levels also correlated with emotion perception in women, but not men. These results echo previous animal studies that find sex-specific differences in responses to oxytocin, and reiterated the idea that the who, when, and how of oxytocin treatment may matter.—Michele Solis.

Most of the speakers at the SIRS session spoke of an involvement of oxytocinergic dysfunction in social deficits of schizophrenic patients. But oxytocin may be involved in the pathogenesis of schizophrenia in many other ways. For example, the mentioned improvement of odor discrimination may be caused by an increase in neurogenesis in the olfactory bulb. Oxytocin enhances neurogenesis, increases BDNF levels (Ayfer et al., 2011), and preserves granule cells from the deleterious effects of stress hormones (Leuner et al., 2012). Perhaps insufficient neurogenesis is the core component of schizophrenia pathogenesis. Tamminga et al. (Tamminga et al., 2010) have formulated a model according to which reduced neurogenesis in the dentate gyrus produces hyperactivation of the CA3 region and generates inappropriate associations, misinterpretation of events, false or illogical memories, and susceptibility to psychosis.

Oxytocin can also activate hippocampal GABAergic interneurons and inhibit excitation of pyramidal cells (Zaninetti et al., 2000). In the adult dentate gyrus, GABA is excitatory in newborn neurons due to their high intracellular Cl- concentration (Aimone et al., 2010). Oxytocin promotes an inhibitory action of GABA by reducing activity of the chloride co-transporter NKCC1 (Mazzuca et al., 2011). Perhaps oxytocin insufficiency results in excitotoxic damage of immature granule cells, especially during stress. Lodge and Grace (Lodge and Grace, 2011) have demonstrated that psychological stress and hyperactivation of the anterior hippocampus can result in enhanced activity of dopamine neurons and psychotic symptoms. Since oxytocin diminishes both cortisol and behavioral responses to stress (Kosfeld et al., 2005), its administration to patients with schizophrenia could be beneficial.

The field seems to be cautiously returning to look seriously at psychotherapeutic approaches. Paying attention to forms of cognition and affect has been a traditional form of therapy, and it seems foolish to ignore the clinical experiences of its many practitioners, despite conceptual problems of past work. We also have the benefits of studies indicating the effects of trauma on subsequent psychosis and developmental research on attachment and language that may mediate early neglect or trauma. Problems in development of TOM in insecure attachment may point to specific vulnerabilities.